Marcel Seiz

[18F]-fluoro-ethyl-l-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma

BACKGROUND To assess the sensitivity and specificity of [(18)F]-fluoro-ethyl-l-tyrosine ((18)F-FET) PET in brain tumors and various non-neoplastic neurologic diseases. METHODS We retrospectively evaluated (18)F-FET PET scans from 393 patients grouped into 6 disease categories according to histology (n = 299) or distinct MRI findings (n = 94) (low-grade/high-grade glial/nonglial brain tumors, inflammatory lesions, and other lesions). (18)F-FET PET was visually assessed as positive or negative. Maximum lesion-to-brain ratios (LBRs) were calculated and compared with MRI contrast enhancement (CE), which was graded visually on a 3-point scale (no/moderate/intense). RESULTS Sensitivity and specificity for the detection of brain tumor were 87% and 68%, respectively. Significant differences in LBRs were detected between high-grade brain tumors (LBR, 2.04 ± 0.72) and low-grade brain tumors (LBR, 1.52 ± 0.70; P < .001), as well as among inflammatory (LBR, 1.66 ± 0.33; P = .056) and other brain lesions (LBR, 1.10 ± 0.37; P < .001). Gliomas (n = 236) showed (18)F-FET uptake in 80% of World Health Organization (WHO) grade I, 79% of grade II, 92% of grade III, and 100% of grade IV tumors. Low-grade oligodendrogliomas, WHO grade II, had significantly higher (18)F-FET uptakes than astrocytomas grades II and III (P = .018 and P = .015, respectively). (18)F-FET uptake showed a strong association with CE on MRI (P < .001) and was also positive in 52% of 157 nonglial brain tumors and nonneoplastic brain lesions. CONCLUSIONS (18)F-FET PET has a high sensitivity for the detection of high-grade brain tumors. Its specificity, however, is limited by passive tracer influx through a disrupted blood-brain barrier and (18)F-FET uptake in nonneoplastic brain lesions. Gliomas show specific tracer uptake in the absence of CE on MRI, which most likely reflects biologically active tumor.

Acute Hypoperfusion Immediately after Subarachnoid Hemorrhage: A Xenon Contrast-Enhanced CT Study

The acute neurological deficit present immediately after subarachnoid hemorrhage (SAH) correlates with overall outcome. Only limited data are available to quantify changes in cerebral perfusion in this acute phase, and this study sought to characterize those changes within the first 12 h post-SAH. Xenon contrast-enhanced CT scanning was performed in 17 patients (Hunt and Hess grade [HH] 1-3, n = 9; HH 4-5, n = 8) within 12 h after SAH. Cerebral blood flow (CBF) was analyzed in all cortical and central vascular regions of interest (ROI), as well as infratentorial ROI. Hemodynamic stress distribution (central/cortical ROI) was also calculated. Asymptomatic patients without perfusion deficits served as controls (n = 5), and Glasgow Outcome Scale score (GOS) was determined 3 months after the event. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were within normal limits in all patients. CBF was significantly reduced in all patients with SAH (34 mL/100 g x min) compared to controls (67 mL/100 g x min; p < 0.001). Patients in better clinical condition (HH 1-3) presented with significantly less reduction of CBF (41 mL/100 g x min) compared to patients with more severe hemorrhage (HH 4-5: 24 mL/100 g x min; p < 0.001), and had better outcomes. Changes in perfusion were more pronounced in supratentorial than in infratentorial ROI. Hemodynamic stress distribution was most pronounced in patients with higher HH grade (p < 0.05). The first 12 h after SAH are characterized by persistent, severe reduction of CBF, which in turn correlates with HH grade, but is independent of ICP or CPP. Acute peripheral vasospasm of the microvasculature, not detectable by conventional angiography, may account for this early phase of prolonged hypoperfusion.

Detection of IDH1 mutations in gliomatosis cerebri, but only in tumors with additional solid component: evidence for molecular subtypes

The current WHO classification of brain tumors defines gliomatosis cerebri (GC) as an extensively infiltrating astrocytic glioma involving at least three cerebral lobes. The relation of GC to diffuse astrocytomas and glioblastoma is uncertain. Due to malignant biological behavior, GC is allotted to WHO grade III. Recent reports showed IDH1 mutations in astrocytic and oligodendroglial tumors WHO grades II and III and in secondary glioblastomas with a frequency of up to 90%, whereas IDH1 mutations occurred in only 5% of primary glioblastomas. Here, we examined the frequency of IDH1 mutations in 35 GC samples by direct sequencing, derived cleaved amplified polymorphic sequence analysis and immunohistochemistry. We identified IDH1 mutations in 10/24 (42%) cases, which also included a solid tumor portion (type 2 GC), but not in 11 “classical” cases without solid tumor mass (type 1 GC). TP53 mutations were revealed in two type 2 GC, but not in any type 1 GC, while combined chromosomal losses of 1p and 19q were not found at all. Our data suggest that GC consists of two histological/molecular subtypes, type 1 being clearly distinct from diffuse astrocytoma, and type 2 sharing features with diffuse astrocytoma.

A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01-07)

BACKGROUND Due to the redundancy of molecular pathways simultaneously involved in glioblastoma growth and angiogenesis, therapeutic approaches intervening at multiple levels seem particularly appealing. METHODS This prospective, multicenter, single-arm phase II trial was designed to evaluate the antitumor activity of sunitinib, an oral small-molecule inhibitor of several receptor tyrosine kinases, in patients with first recurrence of primary glioblastoma using a continuous once-daily dosing regimen. Patients received a starting dose of sunitinib 37.5 mg, followed by a maintenance dose between 12.5 mg and 50 mg depending on drug tolerability. The primary endpoint was a 6-month progression-free survival (PFS) rate. Secondary endpoints included median PFS, overall survival (OS), safety/toxicity, quality of life, and translational studies on the expression of sunitinib target molecules. RESULTS Forty participants were included in this study, and no objective responses were detected. PFS6 was 12.5%, median PFS 2.2 months, and median OS 9.2 months. Five participants (12.5%) showed prolonged stable disease ≥6 months with a median PFS of 16.0 months (range, 6.4-41.4 mo) and a median OS of 46.9 months (range, 21.2-49.2 mo) for this subgroup. c-KIT expression in vascular endothelial cells (n = 14 participants) was associated with improved PFS. The most common toxicities were fatigue/asthenia, mucositis/dermatitis, dysesthesias, gastrointestinal symptoms, cognitive impairment, leukoctopenia, and thrombocytopenia. Two participants (5%) terminated treatment due to toxicity. CONCLUSION Continuous daily sunitinib showed minimal antiglioblastoma activity and substantial toxicity when given at higher doses. High endothelial c-KIT expression may define a subgroup of patients who will benefit from sunitinib treatment by achieving prolonged PFS. ClinicalTrials.gov Identifier: NCT00535379.

Non-fusion rates in anterior cervical discectomy and implantation of empty polyetheretherketone cages.

Study Design. A prospective analysis. Objective. Our aim was to assess the radiographically detectable bony fusion in patients with anterior cervical discectomy (ACD) and polyetheretherketone (PEEK)-cage implantation without additional filling. Furthermore, clinical data of patients with and without fusion were compared. Summary of Background Data. PEEK-cage implantation is performed in cervical spinal surgery because of its benefits. However, fusion rates without filling of the cage have not been reported. Methods. Patients selected for ACD with PEEK-cage implantation prospectively underwent plain radiography in anterior-posterior and lateral projections during the postoperative hospital stay and at follow-up. Furthermore, clinical status was evaluated using the Odom scale, the Short Form-36, the Visual Analog Scale (VAS) for arm and neck pain, and the cervical Oswestry score. Fusion status, migration, and subsidence of the PEEK cage were evaluated on the basis of the lateral radiographs. Fusion was confirmed by presence of continuous trabecular bone bridges in the disc space. To exclude an influence of the cage on the evaluation of fusion rates, fusion was evaluated in analogous fashion retrospectively in a control group. Results. A total of 52 patients underwent ACD and interbody fusion. One-level surgery was performed in 44 patients and 2-level surgery in 8 patients. A total of 60 ACD and interbody fusions with a PEEK cage were analyzed. A majority of operations were at the C5/6 level (40 patients, 77%). Cage height was 4 mm in 32 cases, 5 mm in 23 cases, and 6 mm in 5 cases. Bony fusion was present at 43 treated levels (71.7%), whereas at 17 levels (28.3%) no fusion was found. Statistical analysis revealed no significant difference between the fusion and non-fusion groups regarding time to follow-up, implanted cage height. Short Form-36, cervical Oswestry score, VAS arm and neck, or Odom criteria. In the control group, ACD was performed in 29 patients (42 levels; 18 one-level and 12 two-level operations). Bony fusion was present at 30 levels (71.4%), whereas non-fusion was present at 12 treated levels (28.6%). Statistically analysis revealed no significant difference between the study group and the control group regarding time to follow-up or fusion rates. Conclusion. Implantation of empty PEEK cages after ACD shows an unexpectedly low rate effusion according to radiologic criteria, although no statistically significant difference could be observed clinically.

An Intra-Individual Comparison of MRI, [18F]-FET and [18F]-FLT PET in Patients with High-Grade Gliomas

Objectives Intra-individual spatial overlap analysis of tumor volumes assessed by MRI, the amino acid PET tracer [18F]-FET and the nucleoside PET tracer [18F]-FLT in high-grade gliomas (HGG). Methods MRI, [18F]-FET and [18F]-FLT PET data sets were retrospectively analyzed in 23 HGG patients. Morphologic tumor volumes on MRI (post-contrast T1 (cT1) and T2 images) were calculated using a semi-automatic image segmentation method. Metabolic tumor volumes for [18F]-FET and [18F]-FLT PETs were determined by image segmentation using a threshold-based volume of interest analysis. After co-registration with MRI the morphologic and metabolic tumor volumes were compared on an intra-individual basis in order to estimate spatial overlaps using the Spearmans rank correlation coefficient and the Mann-Whitney U test. Results [18F]-FLT uptake was negative in tumors with no or only moderate contrast enhancement on MRI, detecting only 21 of 23 (91%) HGG. In addition, [18F]-FLT uptake was mainly restricted to cT1 tumor areas on MRI and [18F]-FLT volumes strongly correlated with cT1 volumes (r = 0.841, p<0.001). In contrast, [18F]-FET PET detected 22 of 23 (96%) HGG. [18F]-FET uptake beyond areas of cT1 was found in 61% of cases and [18F]-FET volumes showed only a moderate correlation with cT1 volumes (r = 0.573, p<0.001). Metabolic tumor volumes beyond cT1 tumor areas were significantly larger for [18F]-FET compared to [18F]-FLT tracer uptake (8.3 vs. 2.7 cm3, p<0.001). Conclusion In HGG [18F]-FET but not [18F]-FLT PET was able to detect metabolic active tumor tissue beyond contrast enhancing tumor on MRI. In contrast to [18F]-FET, blood-brain barrier breakdown seems to be a prerequisite for [18F]-FLT tracer uptake.

Pharmacokinetic studies of 68Ga-labeled bombesin ( 68Ga-BZH3) and F-18 FDG PET in patients with recurrent gliomas and comparison to grading: Preliminary results

Purpose: Dynamic PET studies with a 68Ga-Bombesin analog, the 68Ga-BZH3, were performed in patients with highly suspected recurrent gliomas to investigate the effect of the receptor scintigraphy on tumor grading. Furthermore, dynamic F-18 Fluorodeoxyglucose (FDG) studies were performed for comparison. Methods: The study consisted of 15 patients with histologically confirmed recurrent gliomas. Dynamic PET scans using 68Ga-BZH3 and FDG were obtained on 2 different days within 1 week. Multivariate analysis was used for the evaluation of the kinetic data. Standardized uptake values were calculated and a compartment (2-tissue) as well as a noncompartment model was used for data evaluation of both tracers. Results: The evaluation includes 6 patients with a WHO II, 6 patients with a WHO III, and 3 patients with a WHO IV recurrent gliomas. Of the 15 patients, 10 patients demonstrated an increased 68Ga-BZH3 uptake visually, 3 of them with a WHO II, 4 with a WHO III, and 3 with a WHO IV tumor. Of the 15 patients, 6 patients revealed an enhanced FDG metabolism visually, 3 of them with a WHO II, and 3 with a WHO III. None of the 3 patients with WHO IV tumor demonstrated an enhanced FDG-uptake. Discriminant analysis based on a combination of FDG influx and binding potential of 68Ga-BZH3 best discriminated between low- and high-grade gliomas with a correct classification rate of 100%. Conclusions: 68Ga-BZH3 seems to be helpful in patients with recurrent gliomas for the differentiation between low- and high-grade gliomas. Overall, the quantitative evaluation was superior to the visual analysis and the parameters of the 68Ga-BZH3 kinetics were more helpful than those of FDG for the differentiation between low- and high-grade gliomas.

Recurrence pattern in glioblastoma multiforme patients treated with anti-angiogenic chemotherapy

PurposeGlioblastoma multiforme is the prototype of an angiogenic tumour. Under experimental conditions, anti-angiogenic therapy strategies lead to an increased invasion. Here we report on the pattern of tumour recurrence in glioblastoma patients treated with an anti-angiogenic chemotherapy.Patients and methodsA total of 32 patients with glioblastoma multiforme and a residual tumour mass after operation were treated with a continuous low-dose chemotherapy with temozolomide and a COX-II inhibitor, a presumably anti-angiogenic therapy.ResultsWhile anti-tumour activity of this therapy regimen was excellent with a mean overall time to progression of 10.4 (±0.9) months and a mean overall survival of 17.8 (±1.5) months, an unusually high rate of distant recurrences was observed (62.5%).ConclusionPatients treated with an anti-angiogenic chemotherapy experience distant recurrences at a higher rate than reported for conventional therapies. This may reflect an anti-angiogenic therapy-induced activation of glioma invasion confirming similar recently published experimental results.

Pharmacokinetic studies of 68 Ga-labeled bombesin ( 68 Ga-BZH 3 ) and F-18 FDG PET in patients with recurrent gliomas and comparison to grading

Purpose: Dynamic PET studies with a 68Ga-Bombesin analog, the 68Ga-BZH3, were performed in patients with highly suspected recurrent gliomas to investigate the effect of the receptor scintigraphy on tumor grading. Furthermore, dynamic F-18 Fluorodeoxyglucose (FDG) studies were performed for comparison. Methods: The study consisted of 15 patients with histologically confirmed recurrent gliomas. Dynamic PET scans using 68Ga-BZH3 and FDG were obtained on 2 different days within 1 week. Multivariate analysis was used for the evaluation of the kinetic data. Standardized uptake values were calculated and a compartment (2-tissue) as well as a noncompartment model was used for data evaluation of both tracers. Results: The evaluation includes 6 patients with a WHO II, 6 patients with a WHO III, and 3 patients with a WHO IV recurrent gliomas. Of the 15 patients, 10 patients demonstrated an increased 68Ga-BZH3 uptake visually, 3 of them with a WHO II, 4 with a WHO III, and 3 with a WHO IV tumor. Of the 15 patients, 6 patients revealed an enhanced FDG metabolism visually, 3 of them with a WHO II, and 3 with a WHO III. None of the 3 patients with WHO IV tumor demonstrated an enhanced FDG-uptake. Discriminant analysis based on a combination of FDG influx and binding potential of 68Ga-BZH3 best discriminated between low- and high-grade gliomas with a correct classification rate of 100%. Conclusions: 68Ga-BZH3 seems to be helpful in patients with recurrent gliomas for the differentiation between low- and high-grade gliomas. Overall, the quantitative evaluation was superior to the visual analysis and the parameters of the 68Ga-BZH3 kinetics were more helpful than those of FDG for the differentiation between low- and high-grade gliomas.

Feasibility of intraventricular nicardipine prolonged release implants in patients following aneurysmal subarachnoid haemorrhage.

Objective. Intracisternal nicardipine prolonged release implants (NPRI) have been shown to be effective in the prophylaxis of cerebral vasospasm (VS). However, they cannot be used in patients following coil occlusion of the aneurysm. As a certain dissemination of nicardipine within the cerebrospinal fluid (CSF) has been described, we examined the feasibility of intraventricular use of NPRI in patients that underwent clip and coil occlusion of their aneurysms following aneurysmal subarachnoid haemorrhage (aSAH). By comparison with an historical control group, an estimation of their effectivity in regard to angiographic vasospasm and the development of cerebral infarction has been performed. Methods. Thirty-one patients suffering from aSAH were prospectively included in this trial. Study participants received prior to clipping (n = 17) or coiling (n = 14) 6 (n = 15) or 10 NPRI (n = 16) into the lateral ventricles. Physiological data were collected, proximal and global VS were determined using pre-operative and day 8 ± 1 angiography, and incidence of hydrocephalus and VS related infarcts were evaluated and compared to a historical control group consisting of 16 operated patients without NPRI implantation. Results. Intraventricular NPRI were tolerated well. There were no adverse side effects detectable, physiological variables such as heart rate (HR), mean arterial blood pressure (MAP), intracranial pressure (ICP) and electrolytes showed no difference compared to control. There was no difference in the proportion of patients that required CSF shunting. A significant positive angiographic effect could only be observed in clipped patients (proximal vessel diameters: control, 80 ± 30%; NPRI 90 ± 24%; incidence of moderate/severe global VS: control, 73%; NPRI, 41%). Conclusions. The use of intraventricular NPRI seems to be safe and tolerated well. There is preliminary evidence for effectivity on angiographic VS for clipped patients only. A further increase of the effective dose might also exert efficacy in the subset of patients following coil occlusion.